Myocardial fibrosis is a key mechanism of left ventricular decompensation in aortic stenosis and can be quantified using cardiovascular magnetic resonance (CMR) measures such as extracellular volume ...fraction (ECV%). Outcomes following aortic valve intervention may be linked to the presence and extent of myocardial fibrosis.
This study sought to determine associations between ECV% and markers of left ventricular decompensation and post-intervention clinical outcomes.
Patients with severe aortic stenosis underwent CMR, including ECV% quantification using modified Look-Locker inversion recovery–based T1 mapping and late gadolinium enhancement before aortic valve intervention. A central core laboratory quantified CMR parameters.
Four-hundred forty patients (age 70 ± 10 years, 59% male) from 10 international centers underwent CMR a median of 15 days (IQR: 4 to 58 days) before aortic valve intervention. ECV% did not vary by scanner manufacturer, magnetic field strength, or T1 mapping sequence (all p > 0.20). ECV% correlated with markers of left ventricular decompensation including left ventricular mass, left atrial volume, New York Heart Association functional class III/IV, late gadolinium enhancement, and lower left ventricular ejection fraction (p < 0.05 for all), the latter 2 associations being independent of all other clinical variables (p = 0.035 and p < 0.001). After a median of 3.8 years (IQR: 2.8 to 4.6 years) of follow-up, 52 patients had died, 14 from adjudicated cardiovascular causes. A progressive increase in all-cause mortality was seen across tertiles of ECV% (17.3, 31.6, and 52.7 deaths per 1,000 patient-years; log-rank test; p = 0.009). Not only was ECV% associated with cardiovascular mortality (p = 0.003), but it was also independently associated with all-cause mortality following adjustment for age, sex, ejection fraction, and late gadolinium enhancement (hazard ratio per percent increase in ECV%: 1.10; 95% confidence interval 1.02 to 1.19; p = 0.013).
In patients with severe aortic stenosis scheduled for aortic valve intervention, an increased ECV% is a measure of left ventricular decompensation and a powerful independent predictor of mortality.
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Aortic stenosis is accompanied by progressive left ventricular hypertrophy and fibrosis. We investigated the natural history of these processes in asymptomatic patients and their potential reversal ...post-aortic valve replacement (AVR).
Asymptomatic and symptomatic patients with aortic stenosis underwent repeat echocardiography and magnetic resonance imaging. Changes in peak aortic-jet velocity, left ventricular mass index, diffuse fibrosis (indexed extracellular volume), and replacement fibrosis (late gadolinium enhancement LGE) were quantified.
In 61 asymptomatic patients (43% mild, 34% moderate, and 23% severe aortic stenosis), significant increases in peak aortic-jet velocity, left ventricular mass index, indexed extracellular volume, and LGE mass were observed after 2.1±0.7 years, with the most rapid progression observed in patients with most severe stenosis. Patients with baseline midwall LGE (n=16 26%; LGE mass, 2.5 g 0.8-4.8 g) demonstrated particularly rapid increases in scar burden (78% 50%-158% increase in LGE mass per year). In 38 symptomatic patients (age, 66±8 years; 76% men) who underwent AVR, there was a 19% (11%-25%) reduction in left ventricular mass index (
<0.0001) and an 11% (4%-16%) reduction in indexed extracellular volume (
=0.003) 0.9±0.3 years after surgery. By contrast midwall LGE (n=10 26%; mass, 3.3 g 2.6-8.0 g) did not change post-AVR (n=10; 3.5 g 2.1-8.0 g;
=0.23), with no evidence of regression even out to 2 years.
In patients with aortic stenosis, cellular hypertrophy and diffuse fibrosis progress in a rapid and balanced manner but are reversible after AVR. Once established, midwall LGE also accumulates rapidly but is irreversible post valve replacement. Given its adverse long-term prognosis, prompt AVR when midwall LGE is first identified may improve clinical outcomes.
URL: https://www.clinicaltrials.gov. Unique identifiers: NCT01755936 and NCT01679431.
Particle physics today faces the challenge of explaining the mystery of dark matter, the origin of matter over anti-matter in the Universe, the origin of the neutrino masses, the apparent fine-tuning ...of the electro-weak scale, and many other aspects of fundamental physics. Perhaps the most striking frontier to emerge in the search for answers involves new physics at mass scales comparable to familiar matter, below the GeV-scale, or even radically below, down to sub-eV scales, and with very feeble interaction strength. New theoretical ideas to address dark matter and other fundamental questions predict such feebly interacting particles (FIPs) at these scales, and indeed, existing data provide numerous hints for such possibility. A vibrant experimental program to discover such physics is under way, guided by a systematic theoretical approach firmly grounded on the underlying principles of the Standard Model. This document represents the report of the FIPs 2022 workshop, held at CERN between the 17 and 21 October 2022 and aims to give an overview of these efforts, their motivations, and the decadal goals that animate the community involved in the search for FIPs.
Lipoprotein(a) (Lpa) is the preferential lipoprotein carrier of oxidized phospholipids (OxPLs) and a well-established genetic risk factor for calcific aortic valve stenosis (CAVS). Whether Lp(a) ...predicts aortic valve microcalcification in individuals without CAVS is unknown. Our objective was to estimate the prevalence of elevated Lp(a) and OxPL levels in patients with CAVS and to determine if individuals with elevated Lp(a) but without CAVS have higher aortic valve microcalcification.
We recruited 214 patients with CAVS from Montreal and 174 patients with CAVS and 108 controls from Québec City, Canada. In a second group of individuals with high (≥75 nmol/L, n = 27) or low (<75 nmol/L, n = 28) Lp(a) levels, 18F-sodium fluoride positron emission tomography/computed tomography was performed to determine the difference in mean tissue-to-background ratio (TBR) of the aortic valve.
Patients with CAVS had 62.0% higher Lp(a) (median = 28.7, interquartile range 8.2-116.6 vs 10.9 3.6-28.8 nmol/L,
0.0001), 50% higher OxPL-apolipoprotein-B (2.2 1.3-6.0 vs 1.1 0.7-2.6 nmol/L,
0.0001), and 69.9% higher OxPL-apolipoprotein(a) (7.3 1.8-28.4 vs 2.2 0.8-8.4 nmol/L,
0.0001) levels compared with individuals without CAVS (all
0.0001). Individuals without CAVS but elevated Lp(a) had 40% higher mean TBR compared with individuals with low Lp(a) levels (mean TBR = 1.25 ± 0.23 vs 1.15 ± 0.11,
= 0.02).
Elevated Lp(a) and OxPL levels are associated with prevalent CAVS in patients studied in an echocardiography laboratory setting. In individuals with elevated Lp(a), evidence of aortic valve microcalcification by 18F-sodium fluoride positron emission tomography/computed tomography is present before the development of clinically manifested CAVS.
Cores covering the last 6000 years were recovered from two marshes from south-western France. They were studied in an attempt to build a reliable regional record of heavy metal pollution. The cores ...were dated using
14C and historical data. Both Pb concentrations and Pb isotopic composition (
206Pb/
207Pb and
208Pb/
206Pb) were measured in bulk sediment samples using the inductively coupled plasma-mass spectrometer technique. The evolution of the
206Pb/
207Pb ratio recorded in both marshes reveals a good correlation with the worldwide Pb production during the last 5000 years. The lead isotopic records reveal some general trends, along with a few typical events such as the imprints of the pre-anthropogenic background between 6000 and 2300 years BP, the mining activity during the Roman and Greek periods from 2300 to 1700 years BP, the fall of the Roman Empire and the mining activity in Central Europe since the 11th century AD. These results are also consistent with records obtained in other European environments. Consequently, the European atmospheric signal is recorded in these marshes, hiding expected local riverine contributions. Thus, such records may contribute to the construction of a chronological standard curve for continental environments. However, it will be necessary to study other records more accurately dated to obtain an adequate precision before such a reference curve can be set-up.
Abstract
Background
B-type natriuretic peptide (BNP) and aminoterminal-proBNP (NT-proBNP) are well established surrogates of LV function impairment. However, data are scarce regarding their ...prognostic value to risk-stratify patients with classical low-flow, low-gradient aortic stenosis (LFLG-AS, with low left ventricular LV ejection fraction).
Methods
The TOPAS study is a prospective observational cohort of 240 patients with aortic valve area <0.6 cm2/m2, mean gradient<40 mmHg and LVEF<50%. True severe AS was adjudicated using flow independent grading schemes.
Results
BNP significantly predicted one-year (area under the receiver operating-characteristic curve AUC) 0.62±0.04, p=0.026) but not three-year mortality. After adjustment for the severity of AS, initial treatment (aortic valve replacement AVR vs. conservative management ConsRx), age, sex and the EuroSCORE (Model#1), BNP-ratio>550 pg/ml had a trend to predict time to death (HR=2.14 1.00–4.58, p=0.05). In contrast, NT-proBNP ratio significantly predicted both one and three-year mortality (AUC=0.67±0.04 and 0.66±0.05, both p=0.001), and independently predicted time to death (HR=1.39 per 1 unit of Log transformed NT-proBNP 1.11–1.74, p=0.004). In a head-to-head comparison (108 patients with both biomarkers), the AUCs to predict one and thre-year mortality were significantly higher with NT-proBNP versus BNP (p<0.009). NT-proBNP but not BNP independently predicted mortality and significantly improved Model#1 (Likelihood ratio test Chi2=15.95, p<0.001). The category-free net reclassification index of NT-proBNP was 0.71 (p=0.008) versus 0.38 (p=0.15) for BNP. Furthermore, there was a marked survival benefit associated with AVR in patients with NT-proBNP ≥1700 pg/ml (adjusted hazard ratio (aHR) associated to AVR vs conservative management=0.52 0.31–0.85, p=0.009), while those<1700 pg/ml had excellent one-year survival under ConsRx (only one death 4.5±4.4% at one year as compared to 23 37±6.2% for ConsRx-NTproBNP>1700, aHR=0.11 0.01–0.83, p=0.033). The survival benefit associated with AVR interacted with NT-proBNP (p<0.001) but not with true or pseudosevere AS (p=0.53 for interaction), suggesting that NT-proBNP might identify moderate AS patients but sufficiently severe valvulo-ventricular disease to justify AVR.
Survival according to NT-proBNP and AVR
Conclusion
NT-proBNP appears to be an excellent biomarker for the clinical purpose of risk-stratifying classical LFLG-AS. A threshold of 1700 pg/ml i.e. close to the diagnostic threshold for heart failure in acute dyspnea, was a strong independent determinant of the survival benefit associated with aortic valve replacement. Our findings suggest that NT-proBNP should be preferred over BNP.
Acknowledgement/Funding
Canadian Institute of Health Research
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